Document Detail

Epidermal expression of an Elovl4 transgene rescues neonatal lethality of homozygous Stargardt disease-3 mice.
MedLine Citation:
PMID:  21429867     Owner:  NLM     Status:  MEDLINE    
Elongase of very long chain fatty acids-4 (ELOVL4) is the only mammalian enzyme known to synthesize C28-C36 fatty acids. In humans, ELOVL4 mutations cause Stargardt disease-3 (STGD3), a juvenile dominant macular degeneration. Heterozygous Stgd3 mice that carry a pathogenic mutation in the mouse Elovl4 gene demonstrate reduced levels of retinal C28-C36 acyl phosphatidylcholines (PC) and epidermal C28-C36 acylceramides. Homozygous Stgd3 mice die shortly after birth with signs of disrupted skin barrier function. In this study, we report generation of transgenic (Tg) mice with targeted Elovl4 expression driven by an epidermal-specific involucrin promoter. In homozygous Stgd3 mice, this transgene reinstates both epidermal Elovl4 expression and synthesis of two missing epidermal lipid groups: C28-C36 acylceramides and (O-linoleoyl)-omega-hydroxy C28-C36 fatty acids. Transgene expression also restores skin barrier function and rescues the neonatal lethality of homozygous Stgd3 mice. These studies establish the critical requirement for epidermal C28-C36 fatty acid synthesis for animal viability. In addition to the skin, Elovl4 is also expressed in other tissues, including the retina, brain, and testes. Thus, these mice will facilitate future studies to define the roles of C28-C36 fatty acids in the Elovl4-expressing tissues.
Anne McMahon; Igor A Butovich; Wojciech Kedzierski
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-03-22
Journal Detail:
Title:  Journal of lipid research     Volume:  52     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-05-16     Completed Date:  2011-09-19     Revised Date:  2014-09-15    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1128-38     Citation Subset:  IM    
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MeSH Terms
Animals, Newborn
Ceramides / genetics,  metabolism*
Chromosome Disorders / genetics*,  metabolism,  pathology
Chromosomes, Human, Pair 6 / genetics,  metabolism
Disease Models, Animal
Epidermis / drug effects,  metabolism*,  pathology
Eye Proteins* / genetics,  metabolism
Fatty Acids / genetics,  metabolism*
Founder Effect
Macular Degeneration / congenital,  genetics*,  metabolism,  pathology
Membrane Proteins* / genetics,  metabolism
Mice, Transgenic
Phosphatidylcholines / genetics,  metabolism*
Promoter Regions, Genetic
Protein Precursors / genetics*,  metabolism
Retina / metabolism*,  pathology
Tolonium Chloride / analysis,  pharmacokinetics
Grant Support
EY-020799/EY/NEI NIH HHS; R01 EY-01019480/EY/NEI NIH HHS; R01 EY-018395/EY/NEI NIH HHS; R01 EY019480/EY/NEI NIH HHS; R01 EY019480-01A1/EY/NEI NIH HHS; R01 EY019480-01A1S1/EY/NEI NIH HHS; R01 EY019480-02/EY/NEI NIH HHS
Reg. No./Substance:
0/Ceramides; 0/Elovl4 protein, mouse; 0/Eye Proteins; 0/Fatty Acids; 0/Membrane Proteins; 0/Phosphatidylcholines; 0/Protein Precursors; 15XUH0X66N/Tolonium Chloride; 60108-77-2/involucrin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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